Desensitizing teeth with degradable particles

ABSTRACT

A method for desensitizing a hypersensitive tooth in a patient includes contacting exposed tubules with particles including a degradable material.

This is a divisional of copending application Ser. No. 08/336,486, onNov. 9, 1994 by Thomas C. Masterman and Jean L. spencer forDESENSITIZING TEETH WITH DEGRADABLE PARTICLES.

BACKGROUND OF THE INVENTION

The invention relates to desensitizing teeth.

The dentin layer in a tooth generally contains channels, or tubules,extending from the pulpal surface to the peripheral surface locatedunderneath the enamel and cementum. Loss of enamel and/or gingivalrecession accompanied by loss of cementum may expose these tubules inthe dentin. It has been theorized that these exposed tubules areresponsible, in part, for hypersensitivity to mechanical pressure or hotor cold fluids.

The problem of hypersensitive teeth is well-recognized, and varioustreatments have been proposed in the art. Pashley et al., U.S. Pat. No.4,057,021, describes desensitizing hypersensitive teeth by applying anaqueous solution of alkali metal salts and ammonium oxalate to thesurface of the teeth. Kim, U.S. Pat. Nos. 4,631,185 and 4,751,072describes desensitizing teeth by treatment with potassium salts.Neirinckx, U.S. Pat. No. 4,990,327, describes desensitizing teeth withstrontium ion and fluoride ion. Mason, U.S. Pat. No. 4,992,258,describes desensitizing teeth by applying a dentifrice including amontmorillonite clay. Lutz, U.S. Pat. No. 4,011,309, describes adesensitizing dentifrice composition that includes citric acid, sodiumcitrate, and non-ionic polyol surfactant. Mlkvy et al., U.S. Pat. Nos.3,888,976 and 3,772,431 describe using a zinc or strontium ioncontaining astringent-desensitizing agent in an effervescent mouthwashtablet. Hodosh, U.S. Pat. No. 3,863,006, describes desensitizing teethwith a nitrate salt. Svajda, U.S. Pat. No. 3,689,636, describesdesensitizing teeth with solutions of chloride salts. Rosenthal, U.S.Pat. No. 3,122,483, describes desensitizing teeth with strontium ions.Scheller, U.S. Pat. Nos. 4,634,589 and 4,710,372, describe a dentifricecontaining apatite particles for treating hypersensitive teeth. Tureskyet al., U.S. Pat. No. 5,250,288, describes desensitizing ahypersensitive tooth by treating the surface of the tooth with chargedpolymeric particles.

SUMMARY OF THE INVENTION

The invention features a method for desensitizing a hypersensitive toothin a patient. The method includes contacting the tubules exposed on thesurface of a hypersensitive tooth with particles that contain adegradable material. The particles block or cover the tubules in thedentin layer, which results in desensitization. Importantly,particularly when the particles are composed substantially only of thedegradable material, for the most part nothing remains of the particlesin the mouth or body once the degradable material degrades.

The preferred particles have an average size of between 0.01 micron and3 microns, more preferably between 0.2 micron and 0.6 micron. Theparticles may be microspheres, and may have a charged outer surface thathelp the particles cling to the surface of the tooth and block theexposed tubules. The preferred particles optionally may include anantimicrobial agent absorbed on the surface, as described in U.S. Pat.No. 5,300,290, or dispersed throughout the particles, as described inU.S. Ser. No. 08/322,926, filed Oct. 13, 1994, which is assigned to thesame assignee as the present application. The preferred particles alsooptionally may include an analgesic compound (e.g., benzocaine,barbital), which can be absorbed on the outer surface of the particle asdescribed in U.S. Pat. No. 5,252,577, or dispersed throughout thearticle. These patents and patent application are incorporated byreference herein.

In a preferred method, the surface of the hypersensitive tooth ispolished, and a dispersion of the particles is applied to the polishedsurface for at least one minute. A preferred method of applying theparticles is by brushing the teeth with a toothbrush having bristlesthat include the particles.

Some preferred particles are stable when stored, e.g., as an aqueousdispersion, because the preferred particles have non-porous water-stableexteriors composed of a water-stable material. Some preferredwater-stable materials are disrupted by mechanical stresses, such aschewing, flossing, and brushing. Such water-stable materials includehydrophobic materials like poly(methyl methacrylate), polystyrene,beeswax, carnauba wax, petroleum wax, and similar materials which do notsignificantly degrade when exposed to oral enzymes. Other preferredwater-stable materials degrade when exposed to oral enzymes. Suchmaterials include polyhydroxyalkanoic acids, glycolipids, glycerides,and phospholipids.

In some preferred embodiments, the water-stable material functions asboth a degradable material and a water-stable exterior coating. Aparticularly preferred material for this embodiment is glyceroldistearate.

Preferred degradable polymers include polyglycolic acid, polylacticacid, and copolymers of glycolic acid and lactic acid, and esters ofglycerol like glycerol distearate.

"Degradable material", as used herein, means a material which degradeswithin three months when placed in the mouth of a typical patient. Thematerials degrade as a result of exposure to one or more enzymes thatcommonly are found in the mouth. These enzymes include lipases,proteases, and glucosidases. Specific enzymes include parotid amylase,hyaluronidase, beta-glucoronidace, chondroitin sulfatase, amino aciddecarboxylases, catalase, peroxidase (such as lacto peroxidase),collagenase, and lysozyme.

"Water-stable exterior", as used herein, means that the exterior surfaceof the particle is composed of a material that does not chemicallydegrade or swell when exposed to water. For example, as a result of thewater-stable exterior, if the particle includes an anti-microbial agentor an analgesic, substantially no (i.e., less than 5% by weight)anti-microbial agent or analgesic leaches from the particle when theparticle is placed in distilled water (at a concentration of 10% of thedispersion by weight) at room temperature for a month.

The invention provides an effective, straightforward way to desensitizeteeth. Without being bound to any theory, it is believed that theinvention is effective at least in part because the particles block thetubules in the teeth, making it more difficult for external stimuli likehot or cold temperatures to affect the nerve in the pulp. When some ofthe particles blocking the tubules eventually wash out of the tubules ordegrade, they are easily replenished by an additional application ofparticles.

Other features and advantages of the invention will be apparent from thedescription of the preferred embodiment thereof, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a and 1b are electron micrographs of a dentin surface prior toexposure to the particles of the invention.

FIGS. 2a and 2b are electron micrographs of a dentin surface afterexposure to the particles of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The more preferred particles have an average diameter of less than 0.6micron. Larger particles may not fit as well in dentin tubules, and as aresult may not be as effective at blocking the tubules and desensitizingthe teeth.

The particles include a degradable material. Preferred degradablematerials include polycaprolactone, polydecalactone, poly(sebacicanhydride), sebacic acid-co-1,3-bis(carboxy-phenoxypropane), sebacicacid-co-1,6-bis(carboxyphenoxy-hexane),dedecanoic-co-1,3-bis(carboxyphenoxypropane),dedecanoic-co-1,6-bis(carboxyphenoxyhexane), albumin and derivatives,gelatin and derivatives, starch and derivatives, gum arabic, celluloseand derivatives, polysorbate and derivatives, agarose, lectins,galactose, functionalized nylons (e.g. benzylated), proteins (syntheticand natural), polyorthoesters, polyorthoformate, polyureas,polyurethanes, poly(amide-enamine)s, polyvinylalcohol, polyenolketone(PEK), polyHema, functionalized polyHema, ethylenevinylacetatecopolymers, functionalized polymers and copolymers of lactic andglycolic acid, lactic acid homopolymer, glycolic acid copolymer,copolymers of lactic acid and glycolic acid, polyhydroxybutyrate,poly(esterimides), functionalized silicones, poly(anhydrides),poly(malic acid), and polyhydroxyalkanoic acids from synthetic ornatural sources (e.g., bacterial, fungi and the like).

Other preferred degradable materials include monomeric species and mixedmonomeric/polymeric species such as liposomes, glycolipids, fatty acids,glycerides, carnauba wax, and phospholipids. The degradable materialscan be included in organic/inorganic composites (covalent or mixed) bycombining any of the polymers listed above with minerals such as silica,alumina, kaolin, morierite, cordierite, zirconia minerals and the like;any of the monomeric and monomer/polymer species listed above mixed orcovalently bound with minerals such as silica, alumina, kaolin,morierite, cordierite, zirconia minerals and the like; proteins bound tosilica, titania, and the like; silicon-containing polymers; andpolyhydroxyalkanoic acid:salt complexes. Such particles, when used intoothpaste, may act as an abrasive material, and thus may supplement, orperhaps even replace, the abrasive materials commonly used intoothpastes.

The more preferred degradable materials are polymers such aspolyglycolic acid, polylactic acid, and copolymers of glycolic acid andlactic acid, and esters of glycerol. These polymers are well-known andcommercially available. For example, polyglycolic acid is available fromthe American Cyanamid Company (Dexon®) and Polysciences, Inc.;polylactic acid is available from Polysciences, Inc.; and copolymers ofglycolic acid and lactic acid are available from American CyanamidCompany (Vicryl®), Ethicon, Inc. (Polyglactin 910) and Polysciences.Alternatively, the polymers can be synthesized according to knownprocedures. For example, polyglycolic acid can be prepared employing thering opening polymerization of the dimeric ester of glycolic acid;polylactic acid can be prepared employing the ring openingpolymerization of the dimeric ester of lactic acid; and copolymers ofglycolic acid and lactic acid can be prepared employing the ring openingpolymerization of the corresponding dimeric esters.

Other preferred degradable polymeric materials are commerciallyavailable and/or may be prepared by known procedures.

The particles optionally include a thin, non-porous, water-stablecoating that prevents the particle from degrading or swelling when theparticle is stored or incorporated into aqueous systems. Preferredcoating materials include poly(methyl methacrylate), polystyrene,beeswax, carnauba wax, petroleum wax, polyhydroxyalkanoic acid,glycolipids, glycerides, phospholipids, and glycerol distearate. Thecoating materials may be materials (like polystyrene, waxes, orpoly(methyl methacrylate) that do not degrade when exposed to enzymes inthe mouth, or may be materials (like glycerol distearate,polydroxyalkanoic acid, and glycerides) that do degrade when exposed toenzymes in the mouth. All of these materials are commercially available.Preferably the coating constitutes no more than about 10% of theparticle diameter.

In alternative embodiments, the particles are composed entirely of thedegradable material. The degradable material may be a non-water stablematerial, or may be a material like glycerol distearate that is waterstable but degrades when exposed to mouth enzymes.

The preferred particles can be made by numerous conventional, well-knownmethods. These include solvent evaporation methods, with or without asurface active agent as necessary, coacervation in all its variousforms, pan coating, air-suspension coating, press coating, spray-drying,rotational suspension-separation techniques, melt coating methods,interfacial polymerization, melt-granulation processes and any and allrelated methods that yield the desired particles as described. Suchmethods may or may not use organic solvents. Such methods mayencapsulate from solution, from the melt or in powdered (solid state)form. Once formed, the particles may be chemically modified (e.g.,charged or made magnetic). The particles are then coated with a waterstable material. See, for example, the particle-making andparticle-coating procedures described generally in Parrott,Pharmaceutical Technology, pp. 86-91 (Burgess Pub. Co. 1970); Deasy,Microencapsulation and Related Drug Procedures, pp. 1-60 (Marcel Dekker,Inc. 1984); Muller et al., J. Controlled Release, 20 (1992):237-246;Pekarek et al., Nature, v. 367 (1994):258-60; Muller et al., Pharm.Pharmacol. Lett. v. 3 (1993):67-70; and Juliano (ed.), Drug DeliverySystems (Oxford University Press 1980).

To desensitize a hypersensitive tooth, the tooth surface initially ispolished. The preferred particles then are applied to the polishedsurface. Application can take numerous forms. For example, the particlesmay be applied in the form of an aqueous dispersion that includes, e.g.,between 0.01% and 5% particles by weight, that is agitated against thetooth surface for 1-5 minutes. Alternatively, the surface is exposed toa pressurized jet of the aqueous dispersion e.g., at a pressure of about30 psi for about 20 seconds, or the surface is brushed with bristlesthat are saturated with particles, for 1-3 minutes. Each of theseprocedures, when performed on a tooth that had been removed from themouth, is effective at blocking the exposed tubules in the dentin of thetooth with the particles.

FIGS. 1a, 1b , 2a and 2b show the dentin surface before (1a and 1b ) andafter (2a and 2b) a 5 minute exposure to a 0.5% (by weight) aqueousdispersion of poly(lactide-co-glycolide) ("PLGA") particles. Prior toexposure to the dispersion, the exposed tubules in the dentin are empty;after exposure they are substantially filled with the particles presentin the dispersion. (FIGS. 1a and 2a were both taken at 800×magnifications, and FIGS. 1b and 2b were both taken at 4000×magnifications).

An alternative procedure for applying the particles to the tooth is tosoak a cotton pellet with an aqueous dispersion of the particles, andthen rub the cotton pellet for 1-3 minutes over the polished surface ofthe tooth.

The PLGA particles used in the above example were prepared according tothe following procedure:

1. 100 mg of PLGA (80:20) were dissolved in 5 mL of methylene chloride.

2. 100 mL of a 0.10% polyvinyl alcohol (PVA) solution in water wasprepared. The polyvinyl alcohol was 13,000-23,000 MW and was 87-89%hydrolyzed.

3. The PVA solution was stirred with a Tekmar high speed mechanicalstirrer (24,000/min).

4. The PLGA solution was added all at once to the PVA solution. Thissolution was stirred in a fume hood for 20 min. to drive off themethylene chloride.

5. The resulting suspension was centrifuged. The particles were washedwith distilled water. Micrographs showed that a polydisperse particlesize distribution resulted (0.1-1 μm) and that the particles wereirregular in shape.

Other embodiments are within the claims. For example, the particles canbe included in a dentifrice (toothpaste) or a mouthwash; when thedentifrice or mouthwash contacts the surface of a tooth the particleswill fill in the tubules. This approach can be used, in particular, toreplenish particles that were previously blocking a tubule but have, tosome extent, washed out of the tubule or degraded over time. If amouthwash is used, it may be applied under pressure, using anycommercially available water-jet appliance (e.g., a Braun MO 5000). Theparticles can also be applied, for example, by including them on thebristles of toothbrushes or on dental floss. While the times, pressuresand other conditions given above were preferred in a laboratory settingor home use, these conditions may be varied as desired to adapt them toa clinical setting, provided the time, pressure etc., is adequate toblock the tubules. Effective conditions may be readily determined bythose skilled in the art, e.g. by determining whether a patient's toothis still sensitive after the treatment.

The filling of dentin tubules with the particles can be enhanced byusing particles with a charged outer surface, or by using a swellablematerial like polyvinyl alcohol in the particles. When the particlesinclude a swellable material, the particles preferably comprise awater-stable exterior. Significantly, a coated particle including aswellable material may be sufficiently small to flow readily into thetubules. But during application part or all of the coating deterioratesallowing water to contact the swellable material. As this materialswells the particles become more tightly lodged in the tubule.

In addition, the particles may have an antimicrobial, analgesic or othertherapeutic substance adsorbed on their surface or dispersed throughoutthe interior. These particles provide both the desensitization benefitof this invention, and an anti-microbial benefit or other benefitprovided by the therapeutic agent selected. Examples of preferredantimicrobial agents, and how they may be incorporated throughout theparticles, are described in U.S. Ser. No. 08/322,926, filed Oct. 13,1994.

Thus particles having essentially the same composition, e.g., degradablematerial and anti-microbial agent, can serve two functions, particularlywhen the particles are sufficiently small to fit readily in normal sizeddentin tubules. But the particles may serve only one function (releaseof anti-microbial agent) if the particles are too large to effectivelyclog dentin tubules. A composition, e.g., an oral rinse, may includeparticles that are small enough to serve both functions and particleshaving the same composition that do not desensitize the tooth. Todetermine whether such an oral rinse (or other composition) containsparticles having an average diameter within applicant's preferred (0.01micron to 3 micron) or more preferred (0.2 micron to 0.6 micron) ranges,the particle size distribution of all of the essentially identicallycomposed particles in the composition initially is determined. If atleast 5% of the particles have an average diameter of between 0.01micron and 3 micron, or more preferably between 0.2 micron and 0.6micron, the oral rinse includes particles that have an average particlesize within the applicant's preferred or more preferred range.

What is claimed is:
 1. A method for desensitizing a hypersensitive toothin a mouth of a patient, said hypersensitive tooth comprising exposeddentin tubules extending from a paupal surface to the peripheral surfacelocated under the enamel and cementum of said tooth that is exposed insaid mouth of said patient and whose exposure is responsible forhypersensitivity, said method comprising contacting said surface of saidtooth and said exposed tubules with particles, comprising a degradablematerial, that are sufficiently small to block or clog said dentintubules in an amount effective to thereby desensitize said tooth.
 2. Themethod of claim 1, wherein said particles have an average diameter of0.01 micron to 3 microns.
 3. The method of claim 1, wherein saidparticles have an average diameter of 0.2 micron to 0.6 micron.
 4. Themethod of claim 1, further comprising polishing said surface of saidtooth prior to contacting said tooth with said particles.
 5. The methodof claim 1, wherein said degradable material comprises polyglycolicacid.
 6. The method of claim 1, wherein said degradable materialcomprises polylactic acid.
 7. The method of claim 1, wherein saiddegradable material comprises a copolymer of glycolic acid and lacticacid.
 8. The method of claim 1, wherein said degradable materialcomprises glycerol distearate.
 9. The method of claim 1, wherein saiddegradable material comprises an ester of glycerol.